{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T20:06:15Z","timestamp":1790885175200,"version":"4.1.0"},"reference-count":33,"publisher":"American Society of Hematology","issue":"22","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,11,27]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>Functional high-risk (FHR) multiple myeloma (MM) is defined as an unexpected, early relapse (ER) of disease in the absence of baseline molecular or clinical risk factors (RF), making FHR MM inherently dependent on which RFs were assessed at diagnosis, and what treatment patients received. To establish the true incidence of FHR, we analyzed uniformly treated, transplant-eligible patients from the Myeloma-XI (MyXI) trial that had been profiled for the International Myeloma Society and Working Group (IMS\/IMWG) defined high-risk cytogenetic aberrations (HRCA), and the SKY92 gene expression HR signature (GEP-HR). A total of 135 MyXI patients were studied, with a median follow-up of 88 months; 25 (18.5%) experienced ER, defined as relapse &amp;lt;18 months from maintenance randomization post\u2013autologous stem-cell transplantation. Hereof, 15 (60%) were IMS\/IMWG-HR at diagnosis, of whom 8 were also GEP-HR. Another 6 patients were GEP-HR only and would have been missed by IMS\/IMWG-HR. Among 4 patients with IMS\/IMWG\u2013 and GEP\u2013standard risk, 2 had isolated HR markers at diagnosis, leaving only 2 patients (8% of ER; 1.5% of all) truly meeting all FHR-criteria. Combined IMS\/IMWG-HR and GEP-HR profiling identified 84% of ER, and differentiated long-term outcome across all 135 patients: co-occurring IMS\/IMWG and GEP-HR was associated with very short overall survival compared to the absence of both (HR = 13.1; 95% CI, 6.5-26.1, P &amp;lt; .0001), followed by GEP-HR only (HR = 5.1; 95% CI, 2.4-11.1, P &amp;lt; .0001) and IMS\/IMWG-HR only (HR = 3.2; 95% CI, 1.6-6.2, P = .0007). Our results support more comprehensive baseline diagnostic profiling to identify those at risk of ER upfront. The trials were registered at the ISRCTN Registry as ISRCTN49407852 and at clinicaltrials.gov as #NCT01554852.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2025029987","type":"journal-article","created":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T22:55:04Z","timestamp":1755730504000},"page":"2670-2680","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":12,"title":["Challenging the concept of functional high-risk myeloma through transcriptional and genetic profiling"],"prefix":"10.1182","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-0609-2644","authenticated-orcid":false,"given":"Sina A.","family":"Beer","sequence":"first","affiliation":[{"name":"1Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom"},{"name":"2Department of Haematology, The Royal Marsden Hospital, London, United 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Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elsa","family":"Ferris","sequence":"additional","affiliation":[{"name":"1Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1717-0412","authenticated-orcid":false,"given":"Gordon","family":"Cook","sequence":"additional","affiliation":[{"name":"3Leeds Cancer Research UK Clinical Trials Unit, Leeds Institute of Clinical Trials Research, Leeds, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Drayson","sequence":"additional","affiliation":[{"name":"5Department of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Boyd","sequence":"additional","affiliation":[{"name":"1Division of Genetics and Epidemiology, The Institute 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Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2901-0742","authenticated-orcid":false,"given":"Michael","family":"Hubank","sequence":"additional","affiliation":[{"name":"6Clinical Genomics Department, Molecular Diagnostics, The Royal Marsden Hospital, Sutton, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Houlston","sequence":"additional","affiliation":[{"name":"1Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graham","family":"Jackson","sequence":"additional","affiliation":[{"name":"10Department of Haematology, Newcastle University, Newcastle upon Tyne, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3677-4804","authenticated-orcid":false,"given":"Martin 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